Kinins and their B1 and B2 receptors as potential therapeutic targets for pain relief

Brusco, Indiara; Fialho, Maria Fernanda Pessano; Becker, Grace Vieira; Brum, Evelyne da Silva; Silva, Amanda Favarin da; Marchezin, Lara Panazollo; Serafini, Patrick Tuzi; Oliveira, Sara Marchesan

doi:10.1016/j.lfs.2022.121302

Cited by 10 publications

(14 citation statements)

References 174 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Kallikrein produces bradykinin by acting on high-molecular-weight kininogens; therefore, kallikrein inhibitors suppress the subsequent bradykinin-mediated responses. [15] Kallikrein inhibitors berotralstat [20] and lanadelumab [21] are an oral formulation and a subcutaneous formulation with a considerably longer duration of effect, respectively.…”

Section: Discussionmentioning

confidence: 99%

“…[1] Bradykinin is an endogenous substance that causes pain. [15] Since predominant kinin-producing activity is detected in the skin during thermal sweating, bradykinin may play a role in pain during sweating stimulation. [7][8][9][10] Icatibant, a bradykinin B2 receptor antagonist, has been approved for the treatment of acute attacks of hereditary angioedema, [14,16] but been off-label for dermal pain associated with sweating stimuli.…”

Section: Discussionmentioning

confidence: 99%

“…[1] ACE is an enzyme involved in the kallikrein/kinin system that degrades and inactivates bradykinin. [15] By analyzing the dynamics of these molecules before and after thermal sweating, we will evaluate the relationship between dermal pain occurrence, histamine in circulation, and the kallikrein-kinin system. Additionally, to explore the pathomechanism of dermal pain, we will examine histological changes of the eccrine sweat glands at the site of dermal pain in patients who provide consent for a skin biopsy.…”

Section: Discussionmentioning

confidence: 99%

See 2 more Smart Citations

A single-blind, randomized, crossover study on the efficacy of icatibant for sweating-induced dermal pain (icatibant for sweating-induced dermal pain)

et al. 2023

View full text Add to dashboard Cite

Introduction: Severe dermal pain triggered by sweating stimuli, such as bathing, exercise, and mental stress, significantly affects patients’ daily lives. The pathomechanism underlying the sweating-induced dermal pain remains poorly understood and there exists no standard treatment for such pain. This study aims to evaluate the effectiveness of icatibant as an analgesic, a bradykinin B2 receptor antagonist, in treating sweating-induced dermal pain, and to establish the role of bradykinin in pain induction. Methods/design: A multicenter, exploratory, crossover, single-blinded, placebo-controlled randomized, comparative study will be conducted to evaluate the efficacy of subcutaneous icatibant injection (30 mg) in treating sweating-induced dermal pain. Ten patients will be enrolled and assigned randomly in a 1:1 ratio to either the icatibant-placebo or placebo-icatibant groups. The primary endpoint is the change in the visual analog scale scores for dermal pain induced by thermal load before and after treatment with icatibant or placebo. Secondary endpoints include changes in the duration of dermal pain, blood and plasma histamine levels, serum angiotensin-converting enzyme levels, and histological evaluation of skin tissue samples at the site of dermal pain. Discussion: The effectiveness of icatibant against sweating-induced dermal pain would provide clear evidence for the involvement of the bradykinin-bradykinin B2 receptor pathway in the pathogenesis of this condition. This finding may contribute to a better understanding of the underlying mechanisms of dermal pain associated with sweating stimuli and has the potential to improve patients’ quality of life by suggesting potential treatment options, specifically, using drugs that inhibit bradykinin or suppress its production.

show abstract

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

A single-blind, randomized, crossover study on the efficacy of icatibant for sweating-induced dermal pain (icatibant for sweating-induced dermal pain)

et al. 2023

View full text Add to dashboard Cite

show abstract

“…Plasma kallikrein cleavage of HMWK releases the nonapeptide BK (Arg-Pro-Pro-Gly-Phe-Ser-Pro-Phe-Arg), while tissue kallikrein acts on LMWK, generating kallidin or LysBK (Lys-Arg-Pro-Pro-Gly-Phe-Ser-Pro-Phe-Arg) [ 32 ]. These kinins can be further degraded by M- or N-type carboxypeptidases, which remove an arginine (Arg) from their C-terminal region, generating des-Arg-BK and Lys-des-Arg-BK [ 33 , 34 ].…”

Section: The Kallikrein–kinin Proteolytic System and Bradykinin Effectsmentioning

confidence: 99%

Potential Pathways and Pathophysiological Implications of Viral Infection-Driven Activation of Kallikrein–Kinin System (KKS)

Coelho,

Augusto,

Arruda

2024

Viruses

View full text Add to dashboard Cite

Microcirculatory and coagulation disturbances commonly occur as pathological manifestations of systemic viral infections. Research exploring the role of the kallikrein–kinin system (KKS) in flavivirus infections has recently linked microvascular dysfunctions to bradykinin (BK)-induced signaling of B2R, a G protein-coupled receptor (GPCR) constitutively expressed by endothelial cells. The relevance of KKS activation as an innate response to viral infections has gained increasing attention, particularly after the reports regarding thrombogenic events during COVID-19. BK receptor (B2R and B1R) signal transduction results in vascular permeability, edema formation, angiogenesis, and pain. Recent findings unveiling the role of KKS in viral pathogenesis include evidence of increased activation of KKS with elevated levels of BK and its metabolites in both intravascular and tissue milieu, as well as reports demonstrating that virus replication stimulates BKR expression. In this review, we will discuss the mechanisms triggered by virus replication and by virus-induced inflammatory responses that may stimulate KKS. We also explore how KKS activation and BK signaling may impact virus pathogenesis and further discuss the potential therapeutic application of BKR antagonists in the treatment of hemorrhagic and respiratory diseases.

show abstract

“…In this regard, TRPA1 activity may be modulated by kinin receptors that are G protein-coupled receptors (GPCRs). When activated, these receptors stimulate the phospholipase C (PLC) enzyme generating intracellular mediators such as protein kinase C (PKC) [ 30 , 31 ]. Both PLC and PKC are known to sensitise TRPA1 channel [ 32 , 33 , 34 , 35 ].…”

Section: Introductionmentioning

confidence: 99%

Kinin B2 Receptor Mediates Cisplatin-Induced Painful Peripheral Neuropathy by Intracellular Kinase Pathways and TRPA1 Channel Sensitisation

2023

Self Cite

View full text Add to dashboard Cite

Chemotherapy-induced peripheral neuropathy is a severe clinical problem frequently associated with cisplatin use. Although its pathophysiology is poorly understood, it is known that kinin receptors and the transient receptor potential ankyrin 1 (TRPA1) channel play a significant role in the peripheral neuropathy induced by cisplatin in rodents. However, the role of signalling pathways downstream from B2 kinin receptors activation and sensitisation of the TRPA1 channel remains unknown in this model. The cisplatin-induced neuropathy model caused mechanical and cold allodynia in male Swiss mice. Antagonists for kinin B2 and B1 receptors and the TRPA1 channel attenuated the painful parameters. Local sub-nociceptive doses of kinin B2 receptor (bradykinin) and TRPA1 channel (allyl isothiocyanate; AITC) agonists enhanced the painful parameters in cisplatin-treated mice, which their respective antagonists attenuated. Furthermore, we demonstrated the interaction between the kinin B2 receptor and the TRPA1 channel in cisplatin-induced peripheral neuropathy since phospholipase C (PLC) and protein kinase C epsilon (PKCε) inhibitors attenuated the increase in mechanical and cold allodynia evoked by bradykinin and AITC in cisplatin-treated mice. Therefore, regulating the activation of signalling pathways downstream from the kinin B2 receptors activation and TRPA1 channel sensitisation can mitigate the painful peripheral neuropathy decurrent of the oncology treatment with cisplatin.

show abstract

Kinins and their B1 and B2 receptors as potential therapeutic targets for pain relief

Cited by 10 publications

References 174 publications

A single-blind, randomized, crossover study on the efficacy of icatibant for sweating-induced dermal pain (icatibant for sweating-induced dermal pain)

A single-blind, randomized, crossover study on the efficacy of icatibant for sweating-induced dermal pain (icatibant for sweating-induced dermal pain)

Potential Pathways and Pathophysiological Implications of Viral Infection-Driven Activation of Kallikrein–Kinin System (KKS)

Kinin B2 Receptor Mediates Cisplatin-Induced Painful Peripheral Neuropathy by Intracellular Kinase Pathways and TRPA1 Channel Sensitisation

Contact Info

Product

Resources

About